Gene-based analyses of the maternal genome implicate maternal effect genes as risk factors for conotruncal heart defects

Conotruncal and related heart defects (CTRD) are common, complex malformations. Although there are few established risk factors, there is evidence that genetic variation in the folate metabolic pathway influences CTRD risk. This study was undertaken to assess the association between inherited (i.e., case) and maternal gene-gene interactions in this pathway and the risk of CTRD. Case-parent triads (n=727), ascertained from the Children's Hospital of Philadelphia, were genotyped for ten functional variants of nine folate metabolic genes. Analyses of inherited genotypes were consistent with the previously reported association betweenMTHFRA1298C and CTRD (adjustedP=.02), but provided no evidence that CTRD was associated with inherited gene-gene interactions. Analyses of the maternal genotypes provided evidence of aMTHFRC677T/CBS844ins68 interaction and CTRD risk (unadjustedP=.02). This association is consistent with the effects of this genotype combination on folate-homocysteine biochemistry but remains to be confirmed in independent study populations.

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Gene variants in the folate-mediated one-carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.35313 ◽

2012 ◽

Vol 158A (5) ◽

pp. 1124-1134 ◽

Cited By ~ 9

Author(s):

Huiping Zhu ◽

Wei Yang ◽

Wei Lu ◽

Analee J. Etheredge ◽

Edward J. Lammer ◽

...

Keyword(s):

Risk Factors ◽

Carbon Metabolism ◽

Heart Defects ◽

Gene Variants ◽

Conotruncal Heart Defects ◽

One Carbon Metabolism

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Variants in Maternal Effect Genes and Relaxed Imprinting Control in a Special Placental Mesenchymal Dysplasia Case with Mild Trophoblast Hyperplasia

Biomedicines ◽

10.3390/biomedicines9050544 ◽

2021 ◽

Vol 9 (5) ◽

pp. 544

Author(s):

Tien-Chi Huang ◽

Kung-Chao Chang ◽

Jen-Yun Chang ◽

Yi-Shan Tsai ◽

Yao-Jong Yang ◽

...

Keyword(s):

Maternal Effect ◽

Hydatidiform Mole ◽

Placental Tissue ◽

Differentially Methylated Region ◽

Normal Birth ◽

Maternal Effect Genes ◽

Common Etiology ◽

Artificial Abortion ◽

Secondary Dmr ◽

Placental Mesenchymal Dysplasia

Placental mesenchymal dysplasia (PMD) and partial hydatidiform mole (PHM) placentas share similar characteristics, such as placental overgrowth and grape-like placental tissues. Distinguishing PMD from PHM is critical because the former can result in normal birth, while the latter diagnosis will lead to artificial abortion. Aneuploidy and altered dosage of imprinted gene expression are implicated in the pathogenesis of PHM and also some of the PMD cases. Diandric triploidy is the main cause of PHM, whereas mosaic diploid androgenetic cells in the placental tissue have been associated with the formation of PMD. Here, we report a very special PMD case also presenting with trophoblast hyperplasia phenotype, which is a hallmark of PHM. This PMD placenta has a normal biparental diploid karyotype and is functionally sufficient to support normal fetal growth. We took advantage of this unique case to further dissected the potential common etiology between these two diseases. We show that the differentially methylated region (DMR) at NESP55, a secondary DMR residing in the GNAS locus, is significantly hypermethylated in the PMD placenta. Furthermore, we found heterozygous mutations in NLRP2 and homozygous variants in NLRP7 in the mother’s genome. NLRP2 and NLRP7 are known maternal effect genes, and their mutation in pregnant females affects fetal development. The variants/mutations in both genes have been associated with imprinting defects in mole formation and potentially contributed to the mild abnormal imprinting observed in this case. Finally, we identified heterozygous mutations in the X-linked ATRX gene, a known maternal–zygotic imprinting regulator in the patient. Overall, our study demonstrates that PMD and PHM may share overlapping etiologies with the defective/relaxed dosage control of imprinted genes, representing two extreme ends of a spectrum.

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One-carbon metabolite levels in mid-pregnancy and risks of conotruncal heart defects

Birth Defects Research Part A Clinical and Molecular Teratology ◽

10.1002/bdra.23224 ◽

2014 ◽

Vol 100 (2) ◽

pp. 107-115 ◽

Cited By ~ 5

Author(s):

Gary M. Shaw ◽

Wei Yang ◽

Suzan L. Carmichael ◽

Stein Emil Vollset ◽

Charlotte A. Hobbs ◽

...

Keyword(s):

Heart Defects ◽

Conotruncal Heart Defects

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Chromosome 10p13-14 and 22q11 deletion screening in 100 patients with isolated and syndromic conotruncal heart defects

Journal of Medical Genetics ◽

10.1136/jmg.39.4.e16 ◽

2002 ◽

Vol 39 (4) ◽

pp. 16e-16 ◽

Cited By ~ 14

Author(s):

R Voigt

Keyword(s):

Heart Defects ◽

22Q11 Deletion ◽

Conotruncal Heart Defects

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Conotruncal heart defects and chromosome 22q11microdeletion

The Journal of Pediatrics ◽

10.1016/s0022-3476(97)70260-9 ◽

1997 ◽

Vol 130 (4) ◽

pp. 675-676 ◽

Cited By ~ 5

Author(s):

M.Cristina Digilio ◽

Bruno Marino ◽

Aldo Giannotti ◽

Giuseppe Novelli ◽

Bruno Dallapiccola

Keyword(s):

Heart Defects ◽

Conotruncal Heart Defects

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Study of Risk Factors for Conegnital Heart Defect in a Tertiary Level Hospital

Journal of Dhaka Medical College ◽

10.3329/jdmc.v27i1.38946 ◽

2018 ◽

Vol 27 (1) ◽

pp. 51-56

Author(s):

Ferdousi Hossain Poly ◽

Syeda Afroza ◽

Hasanur Rahman ◽

Md Imran Hassan

Keyword(s):

Diabetes Mellitus ◽

Risk Factors ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Maternal Age ◽

Congenital Heart ◽

Heart Defects ◽

Medical College ◽

History Of ◽

The Difference

A congenital heart defect is a heart problem which is present at birth, caused by improper development of the heart during fetal development. In majority of cases there is no known reason for the heart to develop improperly. Some type of congenital heart defects are related to chromosomal abnormality(5-6%), some are to single gene defect(3-5%) or environmental factors(2%). In 85-90% of cases there is no identifiable cause and are generally considered to be caused by multifactorial inheritance. There are some maternal factors which have some role in cardiovascular malformations. These include high maternal age(above 30 years), maternal obesity, consanguinity among the parents, fever during pregnancy, gestational diabetes mellitus, smoking, alcohol consumption, ingestion of any teratogenic drug including homeopathy and herbal medicine. Objective of the study: To evaluate the risk factors associated with congenital heart disease. Methodology: A case control study was conducted at paediatric department of Sir Salimullah Medical College & Mitford Hospital following approval of the protocol from 1st January 2013 to 30th June 2014. Children fulfilling the inclusion criteria-(0-5 year old children of both sexes admitted in paediatric units of Mitford Hospital with any type of congenital heart disease confirmed by echocardiography) were considered as cases. A similar number of age and sex matched children admitted in Mitford Hospital without any cardiac defect were considered as controls. Data were collected by questionnaire. Results: The results show that majority of the cases are male. Maternal age (27.09 ± 4.63) and BMI (24.10 ± 2.28) both are significantly higher in cases than those of controls. Among the cases 31.8% mothers had consanguineous marriage (p=0.001) and 27.1% mothers had history of fever during pregnancy whereas it was present in 9.3% mothers of controls, the difference is significant statistically (p=0.001). Among the cases 34.6% mothers had history of gestational diabetes mellitus and only 18.9% controls had so and the difference is significant statistically (p=0.014). Conclusion: Relatively old age and more weight during pregnancy, consanguinity between parents, fever during pregnancy, history of gestational diabetes mellitus are the main risk factors of congenital heart defects in children J Dhaka Medical College, Vol. 27, No.1, April, 2018, Page 51-56

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